Abstract B cell targeted therapeutics have demonstrated a surprisingly broad potency in autoimmunity, with efficacy demonstrated even in diseases in which T cells are the ultimate mediators of tissue injury. Most of these studies have used B cell depleting antibodies, but alternative approaches targeting signaling pathways in B cells and other antigen presenting cells (APCs) with biologics and small molecule protein tyrosine kinase inhibitors have also met with early clinical success. Mechanistic evidence support two anti&#8208;inflammatory pathways each contributing to the efficacy of targeting the B cell compartment in T cell mediated diseases;1) inhibition of BCR and Fc Receptor (FcR) mediated presentation of self antigen and;2) systemic induction of regulatory B cells. Over the past five years of funding, our NIH/NIDDK supported studies have provided key insights into both of these mechanisms. In animal models of Type I diabetes (T1D) our studies provided proof&#8208;of&#8208;principal for the pathogenic relevance of FcR&#8208;mediated antigen presentation by dendritic cells (DCs). We further demonstrated that targeting the FcR&#8208;associated protein tyrosine kinase SYK in DCs by genetic or pharmacologic means effectively uncouples autoantibodies and enhanced T cell priming in vivo. Use of a clinically relevant SYK inhibitor in the NOD T1D model halted disease progression in NOD mice and protection was associated with both reduced autoreactive T cell priming and the induction of regulatory B cells. Given the importance of SYK in immunoreceptor signaling in myeloid cells and B cells and the early success of SYK inhibitors in the clinic, in this proposal, we will;1) pursue the consequences of interrupting SYK signaling in DCs in T1D models;2) identify the roles of specific activatory FcRs in this process, including the human dendritic cell Fc receptor FcRIIA receptor, and;3) address the mechanism that SYK inhibition induces regulatory B cells in vivo, focusing on the induction of splenic regulatory B cells in the human and mouse.